MX2010011196A

MX2010011196A - Transdermal therapeutic system for administration of fentanyl or an analog thereof.

Info

Publication number: MX2010011196A
Application number: MX2010011196A
Authority: MX
Inventors: Nouha Salman; Ingo Teutsch
Original assignee: Acino Ag
Priority date: 2008-04-25
Filing date: 2009-04-24
Publication date: 2010-12-15
Also published as: EP2111857A1; WO2009130039A1; AU2009240195A1; US20110111013A1; CA2721013A1; JP2011518795A; BRPI0910740A2; AU2009240195B2; CN102014884A; EP2265264A1

Abstract

What is disclosed is a transdermal therapeutic system for administration of an active ingredient through the skin, comprising: (a) a back layer, (b) a reservoir present on the back layer, comprising the active ingredient, polyisobutylene, a gel former and a plasticizer, a portion of the active ingredient in the reservoir being present in the form of undissolved particles and the content of gel formers in the reservoir being at most 4% by weight (based on the total weight of the reservoir), the active ingredient being fentanyl or an analog thereof.

Description

TRANSDERMAL THERAPEUTIC SYSTEM FOR ADMINISTRATION OF FENTANILO OR AN ANALOGUE OF THIS The objective of the present application is a system for the transdermal administration of fentanyl or an analog thereof for therapeutic purposes.

Fentanyl and its analogs, in particular alfentanil, carfentanil, lofentanil, remifentanil, sufentanil, trefentanil, and the related compounds are potent synthetic opiates. Fentanyl and its analogs are highly effective and are metabolized quickly. A problem with fentanyl is its relatively narrow therapeutic index. When the threshold values are exceeded, undesirable side effects occur, in particular the deterioration of respiration which may - unless suitable countermeasures are taken - result in death. The active ingredients are relatively expensive and there is a high risk of abuse. This is why the fentanyl patches on the one hand have to ensure a very precise controlled release of the active ingredient and on the other hand the product must be designed so that the active ingredient can not easily be separated from the patch for the purpose of abuse him.

In general, the transdermal patch is a small adherent band that contains the active ingredient that is to be delivered. These bands can have different shapes and sizes. The simplest type is an adhesive monolith that has a concentrate of the active ingredient (reserve) in a carrier. In general, the reservoir is formed of the active ingredient in a pressure sensitive adhesive accepted for pharmaceutical use. However, it can also be formed of a non-adherent material whose surface contact with the skin is provided with a thin layer of a suitable adhesive. The rate of administration of the active ingredient to the patient from these patches can vary within certain limits from person to person as well as from the place of the skin to the site of the skin depending on the permeability of the skin to the active ingredient.

The most complex patches are laminates or multiple patches with one of active ingredient (which can optionally be dissolved in a liquid) wherein a membrane controlling the release of the active ingredient can be arranged between the reservoir and the adhesive in contact with the skin. This membrane is for the control and optional reduction of the effects of skin permeability variations reducing the rate of in vitro and in vivo release of the active ingredient from the patch.

The deposition of the transdermal patches may contain the active ingredient either completely dissolved in the concentrate or may contain an excess of undissolved active ingredient beyond its saturation concentration (reservoir patch). However, the presence of the undissolved active ingredient or other constituents in a patch can cause stability and other problems in storage as well as in use. One difficulty is also making sure that sufficient active ingredient is dissolved from the solid deposit additionally to replace the active ingredient delivered. In the state of the art, patches of active ingredient whose deposits have solid active ingredient particles are often considered as harmful.

The various transdermal patches for the administration of fentanyl are known from the state of the art. O 02/074286 discloses a transdermal patch with a reservoir containing fentanyl wherein the reservoir has a polymeric composition, preferably polyacrylate in a uniform phase state is without active ingredient not dissolved. Here, supersaturation will be explicitly avoided.

There are many experiments to prepare patches of fentanyl at the base of the polyisobutylene matrix layer. First, those experiments have already been described in the basic patent related to fentanyl patches US-A 4,588,580. This publication describes a transdermal therapeutic system with a polyisobutylene matrix and mineral oil containing a charge of 2% fentanyl. However, in the next period the development starts from the polyisobutylene matrices and if any polyisobutylene matrix was used the attempt was made to completely dissolve the active ingredient in the polyisobutylene matrix.

A transdermal therapeutic system with a polyisobutylene matrix is described in Roy et al., Journal of Pharmaceutical Sciences, vol. 85, No. 5, May 1996, pp. 491 to 495. It is shown that with the concentrations of fentanyl in the polyisobutylene matrix of more than 4% of active ingredient is precipitated and this Roy et al, is obviously considered negative. Roy et al. Suggests that patches for the administration of fentanyl in which fentanyl is present are completely dissolved.

In EP 1 625 854, US 2007/0009588, and US 2006/0013865, the polyisobutylene matrices are suggested, in which case care is taken that the active ingredient is present completely dissolved in the polyisobutylene matrix. The occurrence of crystals in the matrix is considered negative. The systems described herein show a rate of time-dependent release wherein the concentration of fentanyl in a patient's blood rises within the first 20 hours after administration; however, it did not remain constant as desired over a period of at least 2, less at least 3 days, but fell during this period. Those patches are particularly not suitable for administering fentanyl over a larger period of for example, 7 days.

DE 198 37 902 describes the transdermal therapeutic systems in the polyisobutylene base which are particularly suitable for the administration of clonidine; however, fentanyl is also among the active ingredients mentioned. No examples of fentanyl patches are found in this publication; nor is there an indication that the ingredient should be present as a solid in the patches described in this publication. The publication does not contain in vivo investigations in relation to the release of the active ingredient from the patches. The polyisobutylene layer of these patches contains at least 5% by weight of a charger.

Despite all these experiments there is no patch so far on the polyisobutylene base that meets the requirements of the licensing authorities in view of the release of the active ingredient and the attainable plasma levels, respectively and therefore would be marketable.

In view of the state of the art the objective is to provide a transdermal therapeutic system for the administration of fentanyl or an analog thereof through the skin formed on the polyisobutylene base and the one that does not show the problems of the state of the art. In particular, the patch must be capable of releasing fentanyl or an analog thereof, respectively with as short a delay time as possible and in particular stable over a prolonged time, and not present the rate of time-dependent release found with the polyisobutylene systems according to the state of the art. The level in Plasma should remain as constant as possible for as long as possible, but preferably over a period of about 30 hours after administration until about 70 hours after administration, but preferably also for more than 70 hours. In particular, the patch should be adequate to provide analgesia after administration for a period of time greater than 3 days, especially 4 to 7 days and more preferably for about 7 days.

Therefore, the aim of the present invention is a transdermal therapeutic system for the administration of an active ingredient through the skin consisting of: (a) a backup layer; (b) a reserve in the backing layer containing the active ingredient, polyisobutylene, a gel former, and a plasticizer wherein a portion of the active ingredient in the reserve is present in the form of undissolved particles and the content of the former of gel in the reserve is at most 4% by weight (based on the total weight of the reserve), wherein the active ingredient is fentanyl or an analog thereof.

In addition to the fentanyl according to the invention, the preferred fentanyl analogs can be alfentanil, carfentanil, lofentanil, remifentanil, trefentanil or sufentanil wherein it is especially preferred that the active ingredient is fentanyl or sufentanil. In the following, the invention is explained practically with respect to fentanyl. However, the modalities also apply correspondingly to fentanyl analogues.

The construction of a preferred transdermal therapeutic system in the cross section is shown in Fig. 1. The transdermal therapeutic system is covered by means of a cover layer. The backing layer (1) is located at the end of the patch that is in use contrary to the skin. The reservoir (2) is located on one side of the backing layer (1) that faces the human skin. In a preferred embodiment, the transdermal therapeutic system can have a membrane (3). The membrane (3) is arranged between the reservoir (2) and the skin to which the patch is to be applied. If a membrane (3) is present, preferably between the membrane (3) and the skin there is an adhesive layer (4) which is without active ingredient, otherwise but not preferred in this case an adhesive layer can also be applied next to the membrane and for example, you can surround it in a circular way.

In addition there is a laminated layer (5) on the side of the adhesive layer (4) opposite to the deposit (2) that is released before using the transdermal therapeutic system.

In a preferred embodiment of the transdermal therapeutic system a membrane (3) is provided on the side of the reservoir (2) opposite the backing layer which controls the release of the active ingredient. The main purpose of the membrane is to reduce the release rate in vivo and in vitro of the active ingredient from the patch. In this way, differences in the permeability of the active ingredient through the skin can be balanced. Preferably, the membrane is a microporous membrane.

Suitable membranes are known in the state of the art. In a preferred embodiment the membrane may contain or be composed of polypropylene or polyethylene vinyl acetate. A particularly preferred material for the membrane is a microporous polypropylene film.

The thickness of the membrane is not particularly limited and can be, for example, in the range of? Μt? up to ??? μp ?, preferred less than 50μ ??, for example, approximately 25μ ??. The pore size preferably is in the range of 0.001 to 0.025μ ??2, for example in the range of 0.002 to. ?? ??μp ?2, particularly around 0.005μp2. Also the shape of the pores is not limited in particular, a rectangular shape is preferred.

Therefore, a common example of a suitable membrane is a microporous polypropylene film with a thickness of approximately 25μp? and a pore size of approximately 0.12μp? x 0.04μp \, as sold under the brand name Celgard 2400 from Celgard LLC, Charlotte, USA.

Optionally, the membrane can be pre-treated according to known methods.

A layer of adhesive without active ingredient (4) is preferably located between the membrane and the laminated film, which allows adhesion of the patch on the skin. Otherwise, the adhesive layer can also be arranged around the membrane. That adhesive layer can Consisting of various pressure sensitive adhesives known per se wherein preferably polyisobutylene but also other substances such as polybutene, various resins of mineral oil products, or suitable polyacrylates can be used. If a polyisobutylene is used for the adhesive layer as a pressure sensitive adhesive preferably the same polyisobutylene is used as used for the reserve. The adhesive layer may contain the conventional additives for the adhesive layers in the active ingredient patches. The thickness of the adhesive layer (dry thickness) can vary in a range from about 10pm to about 300μ?, preferably between about? μta and about 140μ ?? When the amount of the adhesive layer is related to the weight per area of the patch the amount of the adhesive layer is preferably about 10mg / lOcm 2 to about 50mg / 10cm 2, preferably about 20 to about 40mg / 10cm 2 (ready to use ie, dry patch).

In the adhesive layer or self-adhesive reserve without membrane, respectively there is a laminated layer (release coating) identified with the number 5 in Figure 1. Preferably, the laminated layer is prepared from optionally metallizable polymeric material, as well. Examples of polymeric materials used are preferably polyurethanes, polyvinylacetate, polyvinylidene chloride, polypropylene, polycarbonate, polystyrene, polyethylene, polyethylene terephthalate, polybutylene terephthalate as well as surface paper optionally coated with the corresponding polymers. Preferably, this is a laminated layer that is fluorinated or siliconized on one or both sides. Especially preferred are commercially available fluorinated or siliconized polyester films, such as commercial siliconized products on a Primeliner side ??? μp? and Perlosic LF 75μ ?? (Loparex, NL and Perlen converting AG, Switzerland).

The stock (3) contains the active ingredient, preferably fentanyl, polyisobutylene, a gel former, and a plasticizer wherein the individual components are coupled such that a portion of the active ingredient (fentanyl) in the stock is present in the form of undissolved particles, so that the fentanyl content is above the saturation solubility of fentanyl in the pool so that not all fentanyl dissolves. This applies for the ambient temperature, ie approximately 25 ° C, but preferably both ambient temperature and application temperature (skin temperature), that is, approximately 34 ° C (the temperature of the skin is somewhat below the body temperature) .

The plasticizer is a basically known compound used in the state of the art in transdermal therapeutic systems as a plasticizer. Preferably, the plasticizer is also designed to improve the penetration of the active ingredient through the skin and in a particularly preferred embodiment regulates the solubility of the active ingredient in the reserve so that a certain content of the active ingredient is kept in solution.

Preferably, the plasticizer is mineral oil, linseed oil, octyl palmitate, squalene, squalane, silicone oil, isobutyl myristate, isostearyl alcohol, and oleyl alcohol wherein the mineral oils are the preferred plasticizers. These oils that are also mentioned as thin paraffins are clear, colorless hydrocarbons. They are obtained from petroleum distillation fractions with a boiling point above 300 ° C and are released from the solid hydrocarbons by cooling. They are refined by extraction with solvents as well as by treatment with bleaching earths and / or sulfuric acid. Both mineral oils are chemically and biologically stable, both, and prevent bacterial growth. By suitable fractionation, mineral oils can be obtained which are liquid around body temperature, ie approximately 35 to 37 ° C and are solid at lower temperatures, especially at temperatures below 20 ° C. It is preferable to choose a mineral oil with a liquefaction point of approximately 30-35 ° C.

Preferably, the plasticizer is present in the stock in an amount ranging from 10 to 60% by weight, more preferably from 25 to 50% by weight, in particular ranging from 30 to 40% by weight (based on the total weight of the reserve) .

In the transdermal therapeutic system the reservoir must contain an amount of fentanyl or an analog thereof sufficient to induce analgesia in a human being and maintain it for at least two days, preferably at least three days, more preferably at least 4 days, and in particular about 7 days (based on the patch management point). Preferably, the reservoir contains an amount of fentanyl or an analog thereof sufficient to induce analgesia and maintain it for a period of at least three days, in particular from three to seven days, especially preferably 7 days.

Because a part of the active ingredient is present in the patch according to the invention in undissolved form, the patch is particularly suitable for a very large use even for more than 3 days, for example up to 7 days. Namely, the content of the active ingredient can be easily increased, not being possible in case the parts contain the active ingredient in completely dissolved form. When the fentanyl content increases above the saturation solubility in those patches, it can be expected that the active ingredient will crystallize and have negative effects when released in those systems.

The absolute amount of the active ingredient to be used depends on several factors, in particular the size of the patch to be used and the duration of use. Preferably, the transdermal therapeutic system contains the active ingredient in an amount of 5 to 30% by weight, preferably 5 to 20% by weight, more preferably in an amount of 5 to 15% by weight, based on the total weight of the reserve. Preferably, these resulting weights per unit area range from 20 to 100 gm2, more preferably from 25 to 80 g / m2, particularly in the range of 30 to 70 gm. Preferably, the reserve has a thickness (dry thickness) in the range of 20 to 400μp ?, more preferred in the range of 30 to 200μp \, particularly in the range of 40 to ??? μp ?.

The reservoir of the patch according to the invention also contains a gel former. Preferably, this is a gel former with a particulate structure having a high concentration of polar groups on its surface. These groups cause correspondingly high interfacial tensions towards the oils that are partially compensated by agglomeration of the particles between themselves to the gel backbones. Therefore, the greater the polarity difference between the oils and the skeleton forming surface, the stronger the gel skeletons. According to the invention, it is preferable to employ the highly gel-forming silica or colloidal silica as the gel former. The particle size is preferably in the nano area and is, for example, in the range of 400 to 1500nm, particularly in the area of 500 to lOOOnm. For example, colloidal silica is marketed under the designation Cab-O-Sil® and is a known thickener for mineral oil. Another example for a suitable gel former is bentonite. The sodium carbomer known as the gel former can also be used. Preferably, the gel former is used in an amount of 0.1 to 4.0, more preferably 0.5 to 2.0% by weight, based on the total weight of the stocks.

In a preferred embodiment, the polyisobutylene in the reservoir consists of two different types of polyisobutylene with different molecular weights. This means that one type of polyisobutylene has a peak in the molecular weight distribution that differs from the molecular weight peak of the other type of polyisobutylene. Thus, the two polyisobutylenes have a different average molecular weight (average weight average molecular weight Mw). Preferably, the polyisobutylene (high molecular weight polyisobutylene) has a molecular weight measurement of 150,000 to 10,000,000, especially preferred of 500,000 to 10,000,000, and the second polyisobutylene has a lower molecular weight average (low molecular weight polyisobutylene) in the range from 15,000 to 100,000, preferably from 20,000 to 80,000. As a rule, the mean weight average molecular weight M "is determined through GPC. In particular, the polyisobutylene with the lower molecular weight average is responsible for the stickiness of the patch. The two polyisobutylenes with different molecular weight can be mixed together wherein the ratio of the polyisobutylene with the highest molecular weight to the polyisobutylene with the lower molecular weight is preferably in the range of 0.05: 1 to 20: 1, especially preferred of 0.5: 1 to 2: 1, in particular about 1: 1, however blends of polyisobutylenes with different molecular weights are also commercially available. A particularly suitable commercial product is the product DuroTak®87-616A from National Starch.

In a preferred embodiment also the adhesive layer is a layer of polyisobutylene wherein preferably a mixture of two polyisobutylenes with different molecular weights are used as in the reserve. However, the ratio of the two polyisobutylenes with different molecular weights in the adhesive layer preferably differs from that of the reserve layer. It is particularly preferred that the adhesive layers have been used in the same polyisobutylenes as in the reserve but in a different relationship. Thus, in the adhesive layer the ratio of polyisobutylenes with the molecular weight less than the polyisobutylene with the highest molecular weight is preferably in the range of 10: 7 to 2: 1, preferably 15: 1 to 5: 1, in particular about 10: 1 or 9: 1.

Moreover, the adhesive layer may contain more conventional excipients and additives. When the transdermal therapeutic system has a membrane then in particular the adhesive layer may also contain plasticizers and / or gel formers.

Based on the total weight of the reservoir the part of the polyisobutylene, preferably of both polyisobutylenes with different molecular weights, is preferably 30 to 80% by weight, for example 40 to 65% by weight, preferably 50 to 60% by weight. weight, based on the total weight of the reserve.

Provided that in the context of this description the term "total weight of the reservation" or an amount referring to the reservation, etc., is used. This means the dry weight, that is, the weight of the reserve in the ready patch to be used, unless otherwise described or otherwise evident.

It is important for the transdermal therapeutic systems according to the invention that the pool contains sufficient active ingredient such that it contains active ingredient particles.

In the production of the patch according to the invention the active ingredient is preferably used in a micronized form with an average particle size of 50μp? or less, preferably with an average particle size of 20μp? or less. Also, in the patch reservoir layer (the matrix layer) the active ingredient is present in a micronized form, however, minor deviations in particle size may result from the re-arrangement reactions when the patch is stored. However, also, within the patch the average particle size of the particles of the active ingredient is preferably less than 100 ppm, more preferred less than 50 μπ, and in particular about 20 ppm or less. For the production of the patch according to the invention it is preferable to use micronized fentanyl with an average particle size of lpm or more. Also, the average particle sizes preferably it is found in the patches produced finally. In the reservoir layer of the transdermal therapeutic system the particle size and the particle size distribution of the active ingredient particles can be determined by conventional light microscopy. The evaluation is carried out with conventional computer programs (image processing systems) which, as a rule, are adapted to the microscopes used. Unless indicated or otherwise evident, the particle size refers to the diameter of the particle.

By the micronization process used according to the invention the size of the fentanyl particles is preferably changed so that the average particle size is in the aforementioned ranges. It is also preferable that 100% of the particles are smaller than 50 m, in particular smaller than 20 μp ?. Preferably, approximately 90% of the micronized particles are smaller than 12μ, and approximately 50% of the particles are smaller than ßμ.

There are several methods to determine the particle size and the particle size distribution of the active ingredient, for example the light scattering method as used in Malvern Instruments devices, for example the "Malvern MasterSizer X", the sieve vibration method, mechanical, as used by FMC to determine the size distribution particle size of its AVICEL PH® products, or also the "air-jet" screen analyzes that can be performed with an ALPINA® "air-jet" model 200. Preferably, the determination of particle sizes and distributions It is carried out microscopically by light microscopy and suitable image processing software.

Unless otherwise indicated, the mean particle sizes and particle size distributions are respectively determined with an optical microscope, a camera attached to it, and automated evaluation software. In the present, the proposed test conditions that as a rule are predetermined by the manufacturers of the microscopes have to be met.

If the active ingredient is defined by the indication of the average particle size and the particle size distribution the micronized active ingredient used according to the invention preferably has an average particle size of 20μp? or less, and is it preferred that the active ingredient have a grain size distribution (particle size distribution) where less than 10% of the particles have a size of 25μp? or more and less than 10% of the particles have a size of? μ ?? or less. Another preferred is an active ingredient with an average particle size of 15μp ?. Preferably, that active ingredient has a grain size distribution where less than 2% of the particles have a size of 20μp? or more and less than 50% of the particles have a size of 5μ? t? or less. The grain size distribution for that active ingredient should be as narrow as possible.

On the side of the reservoir that is used out of the human skin there is a backing layer which in the preferred embodiment is occlusive, that is, terminal. In a preferred embodiment, these backing layers may consist of polyolefins, in particular polyethylenes, or polyesters as well as polyurethanes. Also, layers containing several different polymers arranged one on top of the other can be used advantageously. A particularly preferred material for the layer of Backing is a polyolefin marketed by Mylan Technologies, Inc. under the designation Mediflex® 1000. Other suitable materials include cellophane, cellulose acetate, ethyl cellulose, plasticizers containing vinyl acetate-vinyl chloride copolymers, ethylene-vinyl acetate copolymers , polyethylene terephthalate, nylon, polyethylene, polypropylene, polyvinylidene chloride, ethylene-methacrylate copolymer, paper that can optionally be coated, textiles, aluminum film, and polymer-metal composite materials. Especially preferred are polyester films such as polyethylene-teletalate films. The thickness of the backing layer is, for example, ?? at 50μp \, for example of nominal thickness of approximately 20m common in the state of the art.

In the backing layer of the patch there is preferably a cover layer which in particular would prevent the patch from adhering to the package in case small amounts of polyisobutylene or adhesive come out. Preferably, the cover layer is loose in the backing layer and is conserved by electrostatic forces. These layers of coverage are known in the state of the art, for example, from EP 1 097 090, which is incorporated in its entirety for reference. The cover layer is non-adhesive, for example, siliconized or fluorinated on at least the side that is in the backing layer.

The production of a preferred transdermal therapeutic system is carried out by dispersing the components for the reserve, ie, fentanyl and the gel former, in an organic medium such as heptane and mixing the mineral oil and polyisobutylene in an organic medium, preferably the same as before. Then, the fentanyl and the gel former are dispersed in the mixture of polyisobutylene and mineral oil. In the production of the reserve preferably a volatile organic medium is used, for example heptane. Then, the mixture is applied as a uniform layer on the backing layer and dried. If it is desired to apply a membrane, it is applied on the side of the reserve opposite the backing layer.

In a separate operation the adhesive layer (without active ingredient) is optionally applied to the laminated film and allowed to dry.

Subsequently, the components obtained in both processing steps are laminated together in a that the adhesive layer is applied to the membrane, if the membrane was provided. In embodiments where no membrane is used, the adhesive layer is directly laminated to the reservoir (if an adhesive layer is present in this case). After this, the pieces of the desired size can be cut with matrix of the final laminated film and packed.

In the individual processing steps the organic solvents necessary to dissolve the polyisobutylene and to disperse the other constituents are removed by subjecting the products to increasing temperatures, optionally also using a low pressure.

With the transdermal therapeutic system according to the invention the plasma levels can be adjusted very well. Therefore, according to the invention there are preferred transdermal therapeutic systems as described and claimed in this application providing a plasma level in the steady state in the range of 200pg / mL to 500pg / mL, preferred from 250pg / mL to 350pg / mL (pg = peak grams) when administered to a patient. Particularly preferred are those transdermal therapeutic systems as described in this application and claimed in the claims where the following applies: When a regression line is drawn through the plasma level values in the range of 30 hours to 70 hours (at least one measurement point every 5 hours) the value of the plasma level in the regression line in 30 hours it deviates from the plasma level value in the regression line in 70 hours by no more than 10%.

This shows the very high consistency of the plasma level values of fentanyl that can be obtained with the formulations according to the invention.

The following examples explain the invention but do not restrict it.

Example 1 For the production of a transdermal patch in the first fentanyl with an average particle size of 20 μt? (Gesellschaft für Mikronisierung mbH, jet thousand, AS, Hosokawa Alpine AG) was dispersed in heptane with polyisobutylene (DuroTak®87-616A), silica (Cab-O-Sil M-5P) as the gel former, and mineral oil "Klearol" as the plasticizer. The mixture was applied as a thin layer to the backing layer and allowed to dry so that the weight per unit area was about 55g / m2. After this, a microporous polypropylene film (Celgard 2400) was applied as a membrane.

In parallel, only polyisobutylene (DuroTak®87-616A, dissolved in heptane) was applied as a thin layer to the laminated layer and allowed to dry so that a weight per unit area of about 30g / m2 resulted. The tolerance of the weights per unit area was 10%.

After drying both layers were laminated between considering that the membrane was connected to the resin using suitable pressures.

Subsequently, rectangular patches with rounded edges with a size of 10cm2 were cut by matrix and packed with the cover film. The final product had the following composition: Name of the constituent Release Concentration (%) nominal 25pg / h of the reserve Patch size ready to use 10cm2 (dry) Reserve containing fentanyl Fentanyl 95mg 9% DuroTak®87-616A 30. Omg 54.5% Cab-O-Sil M-5P 0.55mg 1% Klearol (mineral oil) 19.5mg 35.5% Heptane * Adhesive layer DuroTak®87-616A 30. Omg 100% Heptane * Layer materials Celgard 2400 10. Ocm2 Hostaphan MN 19 MED 10. Ocm2 Primeliner ??? μ ?? PET C1S 15cm2 PETP film, 36μp ?, 15cm2 transparent Aluminum packaging, 1 bag White * Not present in the final product The components used in the example will be explained in more detail as follows: Designation of chemical description Function component DuroTak®87-616A Polyisobutylene Adhesive Adhesive dissolved in pressure-sensitive n-heptane Cab-O-Sil M-5P Colloidal silica Gel former Klearol Light mineral oil Plasticizer Celgard 2400 Membrane Film Polypropylene microporous Hostaphan MN 19 Terephthalate film MED polyethylene backing layer with a nominal thickness of 19μp? Primeliner Polyester film Laminated layer ??? μp? PET C1S with a nominal thickness of ??? μp ?, one side silicone PETP film, Polyester film 36μp ?, with a nominal thickness of 3μμ transparent coverage, one side silicone Packaging of sealed adhesive packaging Aluminum material, with heat packaging White Example 2 The transdermal patches prepared according to the procedure described in Example 1 were investigated in a pilot study. In the pilot study, six healthy volunteer subjects were employed. Two different patches were tested in total. The control was a product of the state of the art with the designation Durogesic SMAT 25μg / h, a monolithic transdermal system with a polyacrylate matrix. The patch was compared to the patch according to the invention as described in Example 1. Here, the nominal release is 25 μg fentanyl per hour.

The patches were adhered to the subjects and subsequently the concentrations of fentanyl in the blood were measured. Each of the means of six measurements was plotted on the release curve according to Figure 2.

The release curve according to Figure 2 shows that the patch according to the invention (-? - invention) has a concentration of fentanyl clearly higher in the plasma of the subjects and that the concentration remains constant even better on about three days as with the polyacrylate patch that obtained an approval for drugs as a commercial product despite not having a completely constant release.

Therefore, a patch with only 65% of the size of the patch according to the invention has a plasma level in the subjects corresponding to the value of the state of the art in relation to the best constancy as with the polyacrylate patch. These values are also recorded in Figure 2.

The example clearly shows that the transdermal patch according to the invention has considerably improved release compared to a product of the state of the art. Therefore, smaller patches can have the same efficacy as larger patches known from the prior art. In addition, the blood level curve shows that the active ingredient is used more efficiently.

Moreover, it was surprisingly shown that in the patches according to the invention the effect described for the polyisobutylene patches of the state of the art, namely a time dependence of the release within the first 3 days after administration it does not show better but the plasma concentration remains constant over at least 3 days without showing a slow drop in plasma concentration after an initial rapid increase over the first 20 hours. This is surprising and exceptionally advantageous in the polyisobutylene patches according to the invention, which therefore are superior even than the fentanyl-based polyacrylate patches present in the current market.

Claims

1. A transdermal therapeutic system for the administration of an active ingredient through the skin, consisting of: (a) a backup layer; (b) a stock present in the backing layer, which contains the active ingredient, polyisobutylene, a gel forwarder and a plasticizer wherein a part of the active ingredient in the stock is present in the form of undissolved particles and the content of the The gel-forming agent in the reserve is at most 4% by weight (based on the total weight of the reserve), the active ingredient is fentanyl or an analog thereof.

2. The transdermal therapeutic system according to claim 1, characterized in that the active ingredient is fentanyl or sufentanil.

3. The transdermal therapeutic system according to any of claims 1 or 2, wherein a membrane is provided on the side of the reservoir opposite to the backing layer wherein the membrane is a microporous membrane.

4. The transdermal therapeutic system according to any of claims 1 to 3 with a laminated layer (release coating).

5. The transdermal therapeutic system according to claim 4, characterized in that the reservoir contains an amount of fentanyl or an analog thereof sufficient to induce analgesia and to maintain it for a period of three to seven days.

6. The transdermal therapeutic system according to any of claims 1 to 5, characterized in that the plasticizer is a mineral oil.

7. The transdermal therapeutic system according to any of claims 1 to 6, characterized in that the gel former is colloidal silica or bentonite.

8. The transdermal therapeutic system according to any of claims 1 to 7, characterized in that the particles of the active ingredient in the reserve are present in micronized form with an average particle size of d? Μt? or less, in particular of 20μp? or less.

9. The transdermal therapeutic system according to any of claims 1 to 8, characterized in that the polyisobutylene is a mixture of two polyisobutylene polymers with different molecular weights.

10. The transdermal therapeutic system according to any of claims 1 to 9, characterized in that a cover layer is applied to the side of the backup layer opposite the reserve.

11. The transdermal therapeutic system according to any of claims 1 to 10, characterized in that the backing layer is an occlusive backing layer.

12. The transdermal therapeutic system according to any of claims 1 to 11, characterized in that the active ingredient of the reserve is present in a concentration in the range of 3% by weight to 20% by weight, based on the total weight of the the reserve.

13. The transdermal therapeutic system according to any of claims 1 to 12, characterized in that the plasticizer is present in an amount of 10 to 60% in the reserve, based on the total weight of the reserve.

14. The transdermal therapeutic system according to any of claims 1 to 13, characterized in that the polyisobutylene is present in an amount of 30 to 80% in the reserve, based on the total weight of the reserve.

15. The transdermal therapeutic system according to any of claims 1 to 14, characterized in that it has an adhesive layer without undissolved active ingredient.

16. The transdermal therapeutic system according to claim 15, characterized in that the adhesive layer is polyacrylate or a polyisobutylene.

17. The transdermal therapeutic system according to claims 15 or 16, characterized in that the area of the adhesive layer corresponds to the area of the reservoir. SUMMARY OF THE INVENTION A transdermal therapeutic system is described for the administration of an active ingredient through the skin, consisting of: (a) a backup layer, (b) a reserve present in the backup layer, containing the active ingredient, polyisobutylene, a gel former and a plasticizer, a part of the active ingredient in the reserve is present in the form of undissolved particles and the content of the gel formers in the stock is at most 4% by weight (based on the total weight of the stock), the active ingredient is fentanyl or an analog thereof .